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Hoelen, Hanneke; Zaldumbide, Arnaud; van Leeuwen, Wouter F; Torfs, Ellen C W; Engelse, Marten A; Hassan, Chopie; Lebbink, Robert Jan; de Koning, Eelco J; Resssing, Maaike E; de Ru, Arnoud H; van Veelen, Peter A; Hoeben, Rob C; Roep, Bart O; Wiertz, Emmanuel J H J
PloS one, 06/2015, Volume: 10, Issue: 6Journal Article
Patients with type 1 diabetes (T1D) suffer from beta-cell destruction by CD8+ T-cells that have preproinsulin as an important target autoantigen. It is of great importance to understand the molecular mechanism underlying the processing of preproinsulin into these CD8+ T-cell epitopes. We therefore studied a pathway that may contribute to the production of these antigenic peptides: degradation of proinsulin via ER associated protein degradation (ERAD). Analysis of the MHC class I peptide ligandome confirmed the presentation of the most relevant MHC class I-restricted diabetogenic epitopes in our cells: the signal peptide-derived sequence A15-A25 and the insulin B-chain epitopes H29-A38 and H34-V42. We demonstrate that specific silencing of Derlin-2, p97 and HRD1 by shRNAs increases steady state levels of proinsulin. This indicates that these ERAD constituents are critically involved in proinsulin degradation and may therefore also play a role in subsequent antigen generation. These ERAD proteins therefore represent interesting targets for novel therapies aiming at the reduction and possibly also prevention of beta-cell directed auto-immune reactions in T1D.
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